Adipose tissue plays an important role in the pathogenesis of obesity and its associated diseases such as type 2 diabetes, cardiovascular disease and dyslipidemia. Adipose tissue secretes a variety of bioactive factors to regulate energy metabolism. Collectively known as adipocytokines, these factors include leptin, tumor necrosis factor alpha, plaminogen activator inhibitor-1, adiponectin/ACRP30/adipoQ and resistin. Dysregulation of adipocytokines may cause or contribute to the development of obesity and its comorbidities. However, the currently known adipocytokines cannot fully explain the phenotypes of these diseases. For example, why is visceral obesity more pathological than subcutaneous obesity? In an attempt to discover novel visceral adipose genes and to better understand fat cell biology, we sequenced 10,411 expressed sequence tags (ESTs) from a human omental fat library. Bioinformatics analysis revealed that one frequently sequenced EST was a potential secretory factor and Northern analyses revealed that this EST was expressed only in omental, not in subcutaneous adipose tissue. We therefore have named this novel adipocytokine, omentin. Further experiments demonstrated that omentin is indeed a secretory protein and is detectable in human blood. Importantly and unexpectedly, omentin markedly enhances insulin-mediated glucose transport in 3T3-L1 adipocytes and activates Akt, both in the presence and absence of insulin. We hypothesize that omentin is a novel adipocytokine that regulates energy metabolism and insulin signaling. To test this hypothesis, we propose: (1) to determine the mechanism by which omentin increases insulin sensitivity by dissecting the omentin signaling pathway in vitro in 3T3 Ll adipocytes; (2) to determine the in vivo effect of omentin on obesity, insulin resistance and glucose metabolism by administering the recombinant protein to normal and obese/insulin-resistant mice or by administering neutralizing antibodies to normal mice; and (3) to define the role of omentin in humans by measuring serum levels of omentin in 900 subjects enrolled in the Amish Family Diabetes Study, and determining the relationship between serum omentin levels and a variety of metabolic parameters, including obesity, body fat distribution, glucose tolerance, insulin levels, and diabetes. These studies will define the mechanism of action of this novel adipocytokine, as well as its role in fat cell biology, energy regulation, and glucose metabolism. These new insights may lead to new strategies to prevent and treat obesity, insulin resistance and diabetes.